This proposal rests upon the hypothesis that mycobacterial induction of CD4+ T cell anergy leads to loss of sarcoidosis pulmonary function. Use of antimycobacterial therapy normalizes expression of key mediators of CD4+ T cell function, such as p56Lck, leading to increased IL-2 and IFN? production, and restoration of lung function. The transformative nature of this proposal is that it allows us to translate molecular mechanisms identified at the bench to immune function within the host, and ultimately to a clinical endpoint associated with sarcoidosis mortality, absolute FVC. In the intention-to-treat analysis, following 8 weeks of therapy the 15 subjects revealed an increase of 0.24 liters from the baseline absolute FVC of 2.43?0.81 (p=0.028, paired t-test). The eight subjects completing the CLEAR regimen revealed an increase in the absolute FVC of 0.42 liters, reflecting a mean increase in absolute FVC of 16% from baseline. The observed pulmonary improvement was accompanied by an increase in functional capacity and perception of dyspnea that exceeds current sarcoidosis therapeutic options, such as steroids and infliximab. These encouraging efficacy data has led us propose a multicenter, randomized, double-blind, placebo- controlled Phase II investigation of the effects of CLEAR regimen on subjects with chronic, active pulmonary sarcoidosis. Subjects will be required to have systemic responses to ESAT-6 for study entry. The primary endpoint will be change in absolute FVC. Secondary endpoints will include assessments of 6MWD, SGRQ, chest tomography (CT) radiographic changes and effects on T cell biologic function through the induction of IL-2 pathway in sarcoidosis BAL and PBMC. In addition, we will use reporter mycophages to characterize viable mycobacteria within sarcoidosis BAL. The safety profile will be assessed through detection of adverse events and abnormal lab values. The 1o and 2o endpoints will be obtained over a six month interval, laying the foundation for a definitive Phase 3 investigation.